Anhydrous topical skin preparations

ABSTRACT

The present invention provides anhydrous compositions for topical delivery of a medicament comprising (A) a penetration enhancer/solvent selected from the group consisting of alcohol, propylene glycol, or a combination thereof; (B) a humectant/solvent selected from the group consisting of polyethylene glycol, glycerin, sorbitol, xylitol, or any combination of any of the foregoing; and (C) an anhydrous vehicle. In an alternate embodiment, the present invention provides anhydrous compositions for topical delivery of a medicament which comprise (A) a penetration enhancer/solvent selected from the group consisting of alcohol, propylene glycol, or a combination thereof; (B) a humectant/solvent selected from the group consisting of polyethylene glycol, glycerin, sorbitol, xylitol or any combination of any of the foregoing; (C) an anhydrous vehicle; and (D) a medicament. Also provided are methods for topically delivering a medicament to an animal.

CROSS-REFERENCE TO RELATED APPLICATIONS

This patent application is a continuation of U.S. patent applicationSer. No. 10/722,134, filed Nov. 26, 2003, now U.S. Pat. No. 8,232,276,which is a continuation of U.S. patent application Ser. No. 09/562,376filed May 1, 2000, now U.S. Pat. No. 7,179,475, which is acontinuation-in-part of U.S. patent application Ser. No. 09/205,474filed Dec. 4, 1998, now U.S. Pat. No. 6,238,683, the disclosures ofwhich is incorporated herein by reference in their entireties.

FIELD OF THE INVENTION

The present invention relates to topical anhydrous skin preparationshaving high therapeutic efficacy, low toxicity, and the ability totarget or enhance delivery of active agents to the skin, therebyresulting in an improved, high therapeutic index. The invention furtherrelates to methods for making and using such compositions.

BACKGROUND OF THE INVENTION

Alcohols, polyols (such as, for example, propylene glycol), surfactants(such as, for example, sodium lauryl sulfate), preservatives (such as,for example, parabens, such as methyl paraben), acids (such as, forexample, sorbic acid), and solvents, singly or in topical preparations,are known either to induce irritation, sensitization, or allergic skinreactions and/or to be skin penetration enhancers. Humectants (such asfor example, glycerin), solvents (such as, for example, polyethyleneglycol), sunscreens (such as, for example, zinc oxide), and surfactantsare among the entities known to retard skin penetration of activeagents. See, Angleini, G. Contact Dermatitis 7, 1981; Belmonte, J. PharmSci 67: 517, 1978; Catanzaro, J. M. J Am Acad Dermatol 24 (1), 1981;Cooper, J Pharm Sci 73: 1153, 1984; Faucher, J Am Oil Chem Soc 56: 776,1979; Lahti, A. Contact Dermatitis 29, 1993; Trancik, R. J., ContactDermatitis 8, 1982; Wahlberg, J. E. Acta Derm Venereol 64, 1984; Zatz,J. L. J Soc Cosmet Chem 34: 327, 1983.

Patel et al., U.S. Pat. No. 4,855,294, disclose a composition containingglycerin and a method for reducing skin irritation properties of atransdermal (i.e., delivery by actual passage of a drug through the skinor mucosal tissue) drug enhancer composition.

Glucocorticosteroid-based compositions have been used since the 1940'sto treat inflammations of the skin. World Patent Publication No.WO92/18113 discloses a liquid solution containing an antifungal agentand a steroid for use as a mouthwash. Hogi, F. Mykosen 23(8): 426, 1980reports on the activity of ketoconazole in the presence of triaminoleneacetonide. Ketoconazole compositions have more recently been proved tobe effective in the treatment of mycotic infections.

Skin diseases are often characterized by the combination of bothinflammatory conditions and fungal infections, since inflammatoryprocesses of the skin create predisposing conditions for the growth andproliferation of pathogenic microorganisms. Therefore, a singledrug-therapy with an antiinflammatory or an antifungal agent alone isoften insufficient to treat various skin diseases.

U.S. Pat. No. 5,654,293 and EP Patent Publication No. 0 680 328 describea topical oil in water emulsion and pharmaceutical compositionrespectively comprising ketoconazole and an acetonideglucocorticosteroid having a pH above 2.5 and below 6.

However, the stability problems involved combining a 17-ester steroidwith an imidazole antifungal agent are known from U.S. Pat. Nos.5,002,938 and 5,110,809. The preparation of a formulation containingboth ketoconazole and a glucocorticosteroid was hindered by thedestabilization of the steroid in the presence of ketoconazole. Therecontinues to be an unmet clinical need for topically stable,efficacious, and nontoxic therapies targeted to the skin for thetreatment of skin disorders. Therefore, applications of and theopportunity for new methods for making these compositions are needed.

SUMMARY OF THE INVENTION

According to an embodiment of the present invention, there are providedanhydrous compositions for topical delivery of one or more medicaments.These compositions comprise:

(A) a penetration enhancer/solvent selected from the group consisting ofalcohol, propylene glycol, or a combination thereof;

(B) a humectant/solvent selected from the group consisting ofpolyethylene glycol, glycerin, sorbitol, xylitol, or any combination ofany of the foregoing; and

(C) an anhydrous vehicle.

According to an alternate embodiment of the present invention, there areprovided anhydrous compositions for topical delivery of one or moremedicaments which comprise:

(A) a penetration enhancer/solvent selected from the group consisting ofalcohol, propylene glycol, or a combination thereof;

(B) a humectant/solvent selected from the group consisting ofpolyethylene glycol, glycerin, sorbitol, xylitol or any combination ofany of the foregoing;

(C) an anhydrous vehicle; and

(D) one or more medicaments.

According to another embodiment of the present invention, there areprovided methods for topically delivering one or more medicaments to ananimal, such as a mammal or a human patient, in need of the medicaments.The methods comprise topically administering to the animal compositionsas described above.

DETAILED DESCRIPTION OF THE INVENTION

The compositions of the present invention typically are creams, gels,ointments, lotions or liquids. These compositions are anhydrous in thatno water is added. However, a certain amount of water associated withthe various components may be contained in the composition. Typically,this will be less than 10 percent by weight, based upon 100 percent byweight of total composition. Preferably, the present compositions arecompletely anhydrous.

Penetration enhancers/solvents suitable for use in the present inventionare alcohols, including, but not limited to, ethanol, propylene glycol,or a combination thereof. Suitable humectants/solvents for use herein,include, but are not limited to, polyethylene glycol, glycerin,sorbitol, xylitol or any combination of any of the foregoing. Suitableanhydrous vehicles for use herein include, but are not limited to,alcohols which may be the same as or different than the alcoholpenetration enhancer. Non-limiting examples of such alcohols areisobutanol and isopropyl alcohol.

Medicaments which may be delivered topically in the present compositionsinclude, but are not limited to, antifungal agents, antibacterialagents, antiviral agents, antiacne agents, antiaging agents,antipruritic agents, photoprotection agents, skin pigment modulators,hair growth enhancers, hair growth inhibitors, hair removal agents,antidandruff agents, anti-seborrheic agents, anti-psoriasis agents,exfoliating agents, wound healing agents, anti-ectoparasitic agents,sebum modulators, immunomodulators, hormones, botanicals, moisturizers,astringents, cleansers, sensates, antibiotics, anti-irritants,anesthetics, analgesics, steroids, anti-inflammatories, tissue healingsubstances, tissue regenerating substances, vitamins including, but notlimited to, retinoids and the like, amino acids, peptides, minerals,hydroxy acids, including, but not limited to, alpha hydroxy acids andbeta hydroxy acids, or any combination of any of the foregoing.

Non-limiting examples of steroids are glucocorticosteroids andparticularly desonide. A non-limiting example of an antibiotic iserythromycin. Azole-type antifungal and antibacterial agents, such asimidazole antifungal and antibacterial agents, may be employed in thecompositions of this invention in their base form. For example,ketoconazole, miconazole, itraconazole, metronidazole, elubiol, and likerelated imidazole antifungals and antibacterials known to those of skillin the art are useful in the topical formulations of this invention. Apreferred antifungal agent is ketoconazole.

Other components which may be contained in the compositions of thepresent invention include, but are not limited to, emollients, chelatingagents, pH adjusters, antioxidants, gelling agents, viscosifiers,colorants, fragrances, UV stabilizers, sunscreens, or any combination ofany of the foregoing.

Non-limiting examples of pH adjusters are malic acid, lactic acid,citric acid, glycolic acid, benzoic acid, ascorbic acid, or anycombination of any of the foregoing. Non-limiting examples ofantioxidants are propyl gallate, ascorbic acid, ascorbyl palmitate,butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT),tocopherol, such as alpha-tocopherol, or any combination of any of theforegoing. A non-limiting example of a viscosifier is hydroxypropylcellulose.

The amounts of each of the components of the present composition aretypically those amounts effective to accomplish the purpose of thatingredient. For example, the amount of penetration enhancer is typicallya penetration enhancing effective amount. Preferably, the compositionsinclude from about 1.0 to about 50 percent by weight of penetrationenhancer/solvent, from about 10 to about 80 percent by weight ofhumectant/solvent, from 0 to about 10 percent by weight of emollient andaesthetic enhancer combined, from 0 to about 2 percent by weight ofchelating agent and pH adjuster combined, from 0 to about 2 percent byweight of antioxidant, from 0 to about 5 percent by weight of gellingagent and viscosifier combined, and an anhydrous vehicle, based upon 100percent by weight of total composition.

Preferably, the amount of hydroxypropyl cellulose gelling agent willrange from 0 to about 3 percent by weight, based upon 100 percent byweight of total composition.

Preferred amounts of specific medicaments are from about 0.0001 to about20 percent by weight, preferably from about 0.5 to about 3 percent byweight, and most preferably about 2 percent by weight of an antifungalagent and particularly ketoconazole; from about 0.0001 to about 10percent by weight, preferably from about 0.01 percent to about 2.0percent by weight, and most preferably about 0.05 percent by weight, ofa glucocorticosteroid and particularly desonide; preferably from about0.001 to about 0.5 percent by weight, and most preferably from about0.02 to about 0.1 percent by weight of a vitamin and particularly anall-trans retinoic acid, tretonoin; and preferably from about 0.01 toabout 10 percent by weight, and most preferably from about 0.1 to about3 percent by weight of an antibiotic and particularly erythromycin,based upon 100 percent by weight of total composition.

The amount of the penetration enhancer, solvent and vehicle may bebalanced to solubilize the medicament.

The compositions of the present invention are administered topically intherapeutically effective amounts of the medicament incorporatedtherein. The compositions of the present invention may be prepared bymixing the penetration enhancer/solvent, humectant/solvent, andanhydrous vehicle in a primary vessel until uniform. Medicaments oractive agents can then be added and mixed until uniform. Any chelatingagents, pH adjusters, antioxidants, emollients, aesthetic enhancers,fragrances, UV stabilizers, sunscreens, colorants and the like can thenbe added and mixed until uniform. Viscosifiers and gelling agents maythen be added and mixed until uniform. The final product may then bepackaged.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The following examples illustrate the invention without limitation. Allamounts are given by percent by weight based upon 100 percent by weightof total composition, unless noted otherwise.

Example 1

An anhydrous composition for topical administration of ketoconazole anddesonide was prepared having the formulation of Table 1 below.

TABLE 1 Ketoconazole/Desonide Formulation Ingredient % w/w ketoconazole0-2 desonide  0.0-0.05 propylene glycol 20 polyethylene glycol 20glycerin 20 PPG-15 stearyl ether 0-2 hydroxypropyl cellulose 1.5-2.0ascorbic acid 0.0-0.3 citric acid 0.0-0.1 butylated hydroxytoluene0.0-0.1 Ethanol q.s. to 100 

Comparative Examples 1A-C

Compositions having the formulations of Tables 2-4 below were prepared.

TABLE 2 Ketoconazole/Desonide Formulation Ingredient % w/w ketoconazole0-2 desonide  0.0-0.05 propylene glycol 10 stearyl alcohol 4 cetylalcohol 4 sorbitan monostearate 2 polysorbate 60 1.5 mineral oil 1dibasic sodium phosphate 0.25 citric acid 0.24 benzoic acid 0.2butylated hydroxyanisole 0.005 purified water 100

TABLE 3 Ketoconazole/Desonide Formulation Ingredient % w/w ketoconazole0-2   desonide 0.0-0.05  propylene glycol 20 polyethylene glycol 10glycerin 30 PPG-15 stearyl ether  2 hydroxylpropyl cellulose 1.5-2.0  ascorbic acid 0-0.3 citric acid 0-0.1 butylated hydroxytoluene 0-0.1Ethanol q.s. to 100 

TABLE 4 Ketoconazole/Desonide Formulation Ingredient % w/w ketoconazole0-2 desonide  0.0-0.05 propylene glycol 20 N-methyl-2-pyrrolidone 20glycerin 20 PPG-15 stearyl ether  2 hydroxylpropyl cellulose 1.5-2.0ascorbic acid 0.0-0.3 citric acid 0.0-0.1 butylated hydroxytoluene0.0-0.1 Ethanol q.s. to 100 

Example 2

An anhydrous composition for topical administration of all-transretinoic acid as known as tretinoin, was prepared having the formulationof Table 5 below.

TABLE 5 Tretinoin Formulation Ingredient % w/w tretinoin 0.05 propyleneglycol 20 polyethylene glycol 20 glycerin 20 PPG-15 stearyl ether 0-2hydroxylpropyl cellulose 1.5-2.0 citric acid  0.0-0.15 butylatedhydroxytoluene −0.1 Ethanol q.s. to 100

Example 3

An anhydrous composition for topical administration of erythromycin wasprepared having the formulation of Table 6 below.

TABLE 6 Erythromycin Formulation Ingredient % w/w Erythromycin  2propylene glycol 20 polyethylene glycol 20 glycerin 20 PPG-15 stearylether 0-2 hydroxylpropyl cellulose 1.5-2.0 citric acid 0.0-0.5 Ethanolq.s. to 100 

Example 4 and Comparative Example 4A Skin Inflammation Assay

Topically applied phorbol esters are known inducers of skininflammation. Corticosteroids are known to be highly effective inlowering phorbol ester (e.g. TPA) induced inflammation in a dosedependent fashion. Therefore, this model was used to evaluate therelative anti-inflammatory activity of corticosteroids.

Dose response studies to reduce skin inflammation (TPA ear edema in amurine model) were conducted with the compositions of Example 1 (Example4) and Comparative Example 1A (Comparative Example 4A). Results areillustrated in Table 7 below.

TABLE 7 Skin Anti-Inflammatory Activity Example 4 Comparative Example 4% Desonide % Inhibition ED₅₀ (%) % Inhibition ED₅₀ (%) 0.0000 0 0.0015 00.0054 0.0003 30.40 15.36 0.003 57.43 39.05 0.03 87.08 74.79

The composition of Example 1 (Example 4) (ED₅₀=0.0015%) was topicallythree times more active and more potent in its skin anti-inflammatoryactivity than that of Comparative Example 1A (Comparative Example 4A)(ED₅₀=0.0054%).

Example 5 and Comparative Examples 5A and 5B Skin Antifungal Assay

Microbiological in vitro cadaver skin zone of inhibition studies wereconducted to measure antifungal activity and to demonstrate biologicalactivity on the human skin using the compounds of Example 1 (Example 5),Comparative Example 1A (Comparative Example 5A), and NIZORAL® cream (2%ketoconazole cream) (Janssen Pharmaceutica) (Comparative Example 5B).Results are illustrated in Table 8 below.

TABLE 8 Skin Antifungal Activity Clear Zone for Clear Zone for P. ovaleT. rubrum Example 5 11 mm 13 mm Comparative Example 5A  3 mm  0¹Comparative Example 5B  3  0¹ ¹Only a partial zone of inhibition wasnoted for this organism where it continued to grow; no clear zoneresulted.

T. rubrum is a major organism known to cause skin fungal disordersincluding tinea corporis, tinea cruris, and tinea pedis. Resultsindicated that the composition of Example 1 (Example 5) demonstratedsignificant skin antifungal (clear zone) activity against the commondermatophyte T. rubrum. The composition of Comparative Example 1A(Comparative Example 5A) and NIZORAL® cream (Comparative Example 5B) didnot demonstrate clear zone antifungal activity for T. rubrum in thisstudy.

P. ovale has been implicated as playing a major role in the etiology ofvarious dermatoses, such as Seborrheic Dermatitis. The composition ofExample 1 (Example 5) also demonstrated outstanding antifungal activityagainst the yeast, P. ovale, while that of Comparative Example 1A(Comparative Example 5A) and NIZORAL® cream (Comparative Example 5B)only showed minimal activity.

Examples 6 and 7 and Comparative Examples 6A-E and 7A Measurement ofTargeted and Enhanced Delivery to Skin

Franz cell diffusion studies using human cadaver skin were conducted todemonstrate cutaneous bioavailability of medicaments like ketoconazoleand desonide using the compositions of Example 1 (Examples 6 and 7),NIZORAL® cream (Comparative Examples 6A, 6C, and 6E), DesOwen® cream(0.05% desonide cream) (Galderma) (Comparative Examples 7B, 7C, and 7E),Example 1A (Comparative Examples 6B and 7A), and Comparative Example 1B(Comparative Examples 6D and 7F).

Results are illustrated in Tables 9 and 10 below.

TABLE 9 Ketoconazole Targeted Delivery to the Skin Formulation EpidermisDermis Receptor Example 6B 2% ketoconazole, 0.33 ± 0   0.55 ± 0   0.2 ±0  0.05% (desonide) 6C (2% ketoconazole 0.64 ± 0.0 1.18 ± 0.0 0.12 ± 0.0cream) Test 2 6 (2%  2.44 ± 0.65  1.24 ± 0.78  0.5 ± 0.05 ketoconazole,0.05% desonide) 6A (2% ketoconazole 0.205 ± 0.01 0.371 ± 0.10 1.017 ±0.24 cream) Test 3 6D (2%  1.83 ± 0.37  1.77 ± 1.01 0.950 ± 0.43ketoconazole, 0.05% desonide) 6E (2% ketoconazole 0.112 ± 0.03 0.195 ±0.08 0.428 ± 0.15 cream)

TABLE 10 Desonide Targeted Delivery to the Skin Formulation EpidermisDermis Receptor Example 7A 2% ketoconazole, 2.64 ± 0   1.85 ± 0   1.6 ±0  0.05% (desonide) 7B (0.05% desonide 2.57 ± 0   2.03 ± 0   2.99 ± 0  cream) Test 2 7 (2% 1.222 ± 1.35 1.125 ± 0.88 0.677 ± 0.06 ketoconazole,0.05% desonide) 7C (0.05% desonide 1.372 ± 0.21 0.718 ± 0.43 12.49 ±1.83 cream) Test 3 7D (2% 1.359 ± 0.44 1.905 ± 1.09 0.516 ± 0.1 ketoconazole, 0.05% desonide) 7E (2% desonide 0.853 ± 0.03 1.104 ± 0.313.677 ± 1.24 cream)

The composition of Example 1 demonstrated targeted delivery ofketoconazole and desonide to the cutaneous compartments. It deliveredgreater amount of ketoconazole to the epidermis and dermis but less tothe receptor versus NIZORAL® cream. A comparable amount of desonide fromthe composition of Example 1 was delivered to the epidermis and to thedermis and less to the receptor versus DesOwen® cream (ComparativeExamples 7B, 7C, and 7E). Diminished amounts of ketoconazole anddesonide medicaments in the receptor compartment of the composition ofExample 1 may clinically translate to lower systemic absorption of thedrugs and, thereby, lower systemic drug toxicity. The composition ofComparison Example 1A versus NIZORAL® and DesOwen® creams delivered lessketoconazole to the epidermis and dermis but a greater amount to thereceptor versus NIZORAL® cream.

Overall results indicate that the composition of Example 1 resulted intargeted delivery of the drugs to the skin with greater amounts ofmedicaments to the intended sites of the epidermis and dermis versusthat of Comparative Example 1A, NIZORAL® cream and DesOwen® cream. Thedata demonstrates better targeted delivery to the skin and morepharmacologic effects due to the composition of Example 1. Moreover, thecomposition of Example 1 demonstrated positively less permeation throughthe skin into the receptor that could clinically translate into lowersystemic toxicity. In contrast, the composition of Comparative Example1A results indicate greater permeation of ketoconazole into the receptorfluid that could exhibit negative clinical, toxic systemic effects.

Example 8 and Comparative Examples 8A and 8B Cumulative Irritation Test

Dermal irritation studies of the compositions of Example 1 (Example 8),Comparative Example 1B (Comparative Example 8A), and Comparative Example1C (Comparative Example 8B) were conducted on albino rabbits todetermine relative irritation using mean grades of erythema and edema.Results are illustrated in Table 11.

As shown in Table 11, the composition of Example 1 was less irritatingthan that of Comparative Examples 1B and 1C (p<0.05). Glycerin alone didnot singly reduce irritations.

In addition, the combination of the diminished irritation thecomposition of Example 1 and its enhanced efficacy translated into animproved, high Therapeutic Index.

TABLE 11 Cumulative Irritation Test (Combined Daily Erythema and EdemaScore) Day 0 5 10 15 19 Example 8 0 1.6 2.6 1.8 0.7 Comparative Example8A 0 2.4 3.5 3.1 1.3 Comparative Example 8B 0 2.5 3.9 3.1 1.5

Example 9 Repeated Patch Insult Test

The vehicle composition of Example 1, i.e., the composition withoutketaconazole or desonide, was evaluated for the potential to inducecontact dermal sensitization in human subjects.

A total of 216 male and female subjects were evaluated over a period ofsix weeks. After selection, a semi-occlusive patch with test materialwas applied nine times over three weeks. Following a rest period andtest site observation, a challenge test was conducted.

During the induction phase, three subjects exhibited low-levelreactions. Two other subjects exhibited dryness only. Original testsites exhibited no reactions on subjects during the rest period and atthe challenge. Only two subjects exhibited low-level reactions at thechallenge phase.

These clinical results indicate that the vehicle composition of Example1, after repeated application, did not induce contact dermalsensitization in human subjects.

All patents, publications, applications, and test methods mentionedherein are hereby incorporated by reference.

Many variations of the present invention will suggest themselves tothose skilled in the art in light of the above, detailed description.All such obvious variations are within the full intended scope of theappended claims.

The invention claimed is:
 1. An anhydrous composition formulated for topical delivery consisting of: (a) about 20 percent by weight of propylene glycol, (b) about 20 percent by weight of polyethylene glycol, (c) about 20 percent by weight of glycerin, (d) about 34 percent by weight of ethanol, (e) about 2 percent by weight of ketoconazole, (f) PPG-15 stearyl ether, (g) hydroxypropyl cellulose, (h) ascorbic acid, (i) butylated hydroxytoluene, (j) citric acid, and (k) at least one colorant, wherein the composition is formulated as an anhydrous gel.
 2. The composition of claim 1 wherein the ketoconazole is solubilized.
 3. An anhydrous composition formulated for topical delivery consisting of: (a) about 20 percent by weight of propylene glycol, (b) about 20 percent by weight of polyethylene glycol, (c) about 20 percent by weight of glycerin, (d) about 34 percent by weight of ethanol, (e) about 2 percent by weight ketoconazole, (f) PPG-15 stearyl ether, (g) hydroxypropyl cellulose, (h) ascorbic acid, (i) butylated hydroxytoluene, (j) citric acid, and (k) at least one member selected from the group consisting of a colorant, fragrance, UV stabilizer and sunscreen, wherein the composition is formulated as an anhydrous gel.
 4. An anhydrous composition formulated for topical delivery consisting of: (a) about 20 percent by weight of propylene glycol, (b) about 20 percent by weight of polyethylene glycol, (c) about 20 percent by weight of glycerin, (d) about 34 percent by weight of ethanol, (e) about 2 percent by weight ketoconazole, (f) PPG-15 stearyl ether, (g) hydroxypropyl cellulose, (h) ascorbic acid, (i) butylated hydroxytoluene, and (j) citric acid, wherein the composition is formulated as an anhydrous gel.
 5. The composition of claim 3 wherein the ketoconazole is solubilized.
 6. The composition of claim 4 wherein the ketoconazole is solubilized. 